Submissions for variant NM_002755.4(MAP2K1):c.292-3C>T

gnomAD frequency: 0.00007  dbSNP: rs55694358

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198762	SCV000254782	likely benign	RASopathy	2023-11-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825076	SCV000966313	benign	not specified	2018-04-04	criteria provided, single submitter	clinical testing	c.292-3C>T in intron 2 of MAP2K1: This variant is classified as benign because i t is not located within the splice consensus sequence and it has been identified in 0.28% (28/9848) of Ashkenazi Jewish chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs55694358). ACMG/AMP Cr iteria applied: BA1; BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825076	SCV001774631	benign	not specified	2021-07-12	criteria provided, single submitter	clinical testing	Variant summary: MAP2K1 c.292-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a slight impact on normal splicing: Two predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 251428 control chromosomes. The observed variant frequency is approximately 169.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K1 causing Cardiofaciocutaneous Syndrome phenotype (7.5e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.292-3C>T in individuals affected with Cardiofaciocutaneous Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV003456377	SCV004184468	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	MAP2K1: BP4, BS2
Ambry Genetics	RCV004020472	SCV004900352	uncertain significance	Cardiovascular phenotype	2023-10-26	criteria provided, single submitter	clinical testing	The c.292-3C>T intronic alteration consists of a C to T substitution 3 nucleotides before coding exon 3 in the MAP2K1 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004530194	SCV004735375	likely benign	MAP2K1-related disorder	2020-07-21	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).